It is known that microbial metabolite radicicol represented by the following formula (B) has an antifungal effect and an anticancer effect [Nature, 171, 344 (1953); Neoplasma, 24, 21 (1977)] or an immunosuppression effect (Japanese Published Unexamined Patent Application No. 298764/94). ##STR2##
Furthermore, it is known that radicicol derivatives in which the phenolic hydroxyl group is modified with various acyl groups have an antitumor effect (Japanese Published Unexamined Patent Application No. 226991/92). In addition, it is disclosed that radicicol derivatives in which the phenolic hydroxyl group is modified with an acyl group or an alkyl group show an angiogenesis inhibition effect (Japanese Published Unexamined Patent Application No. 279279/94).
Tyrosine kinase is an enzyme which uses ATP as a phosphate donor and catalyzes transfer of its .gamma.-phosphate group to the hydroxyl group of a specified tyrosine residue of a substrate protein, thereby taking an important role in the control mechanism of intracellular signal transduction. Various tyrosine kinase families are known, and it is known that tyrosine kinase activities (e.g., Src in colon cancer, ErbB-2 in breast cancer and gastric cancer, Abb in leukemia, and the like) increase. Disordered increase in the tyrosine kinase activity causes abnormal differentiation and proliferation of cells. In consequence, specific inhibitors of tyrosine kinase are useful in preventing and treating various diseases, including as antitumor agents.
Lck is a tyrosine kinase which is activated when T lymphocytes are activated by antigen stimulation, and an inhibitor of this enzyme is useful as an immunosuppressant. Also, it is known that Src is concerned in bone resorption in osteoclast, and an inhibitor of this tyrosine kinase is useful as a bone resorption inhibitor for the treatment of osteoporosis. In addition, inhibitors of EGF-R (epidermal growth factor receptor), FGF-R (fibroblast growth factor receptor), PDGF-R (platelet-derived growth factor receptor) and the like as receptor type tyrosine kinases of various growth factors are useful as a solid cancer growth inhibitor, an angiogenesis inhibitor, a vascular smooth muscle growth inhibitor and the like.
The inhibitory effect of the tyrosine kinase activity can be measured by carrying out Western blotting analysis with an anti-phosphotyrosine antibody using a rat fibroblast cell strain SR-3Y1 transformed with an oncogene v-Src (available from RIKEN Gene Bank) and calculating the amount of intracellular protein in which tyrosine is phosphorylated. Since the tyrosine phosphorylation level of intracellular protein in SR-3Y1 cells for use in this method is increased by v-Src tyrosine kinase, the ability of radicicol derivatives to inhibit v-Src tyrosine kinase can be detected as reduction of the amount of protein in which tyrosine is phosphorylated. Robinson, S. P. et al. [International Journal of Oncology, 2, 253 (1993)] report a method for examination of tyrosine phosphorylation inhibition effect by Western blotting analysis, and Kwon, H. J. et al. [Cancer Research, 52, 6926 (1992)] report examples of experiment using SR-3Y1 cells.